Tagged: Pink1

Lipid issues in ER = ZZZ issues in PD

New research provides some interesting insight into particular cellular functions – and possibly sleep issues – associated with Parkinson’s.

Researchers in Belgium have recently published interesting findings that a genetic model of Parkinson’s exhibits sleep issues, which are not caused by neurodegeneration, but rather neuronal dysfunction. And as a result, they were able to treat it… in flies at least.

In today’s post, we will review this new research and consider its implications.


Source: Dlanham

I am a night owl.

One that is extremely reluctant to give up each day to sleep. There is always something else that can be done before going to bed. And I can often be found pottering around at 1 or 2am on a week night.

As a result of this foolish attitude, I am probably one of the many who live in a state of sleep deprivation.

I am a little bit nervous about doing the spoon test:

But I do understand that sleep is very important for our general level of health and well being. And as a researcher on the topic, I know that sleep complications can be a problem for people with Parkinson’s.

What sleep issues are there for people with Parkinson’s?

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DUBstop: Oxford-style

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This week multiple research groups at the University of Oxford and Boston-based FORMA Therapeutics announced a collaboration to identify, validate and develop deubiquitinating enzyme (DUB) inhibitors for the treatment of neurodegenerative conditions, like Parkinson’s.

But what exactly are DUB inhibitors? And how do they work?

In today’s post, we will answer these questions, look at what the new collaboration involves, and look at what else is happening with DUB inhibitors for Parkinson’s.


dubstep_color_and_white_by_dtfproductions-d3admfb

Source: Blog4dubstep

Dubstep is a genre of electronic dance music that originated in South London in the late 1990s. Only recently -in the 2010s – has the culture really become more mainstream. And while I have a hard time appreciating the heavy bass music (man, I am becoming a grumpy old man before my time), it is amazing to watch some of the dancers who robotically embody this form of music:

The guy on the right is named Marquese Scott. Sometimes he simply defies the laws of physics.

The title of today’s post is a play on words, because rather than doing ‘Dubstep’ we are going to be discussing how to ‘DUB-stop’.

Researchers in Oxford have recently signed an agreement with a US company to focus resources and attention on a new approach for tackling neurodegenerative conditions, including Parkinson’s.

What they are proposing is a complicated biological dance.

Their idea: to stop deubiquitinating (DUB) enzymes.

What are deubiquitinating enzymes?

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Monthly Research Review – January 2018

Today’s (experimental) post provides something new – an overview of some of the major bits of Parkinson’s-related research that were made available in January 2018.


In January of 2018, the world was rocked by news that New Zealand had become the 11th country in the world to put a rocket into orbit (no really, I’m serious. Not kidding here – Click here to read more). Firmly cementing their place in the rankings of world superpowers. In addition, they became only the second country to have a prime minister get pregnant during their term in office (in this case just 3 months into her term in office – Click here to read more about this).

A happy New Zealand prime minister Jacinda Ardine

In major research news, NASA and NOAA announced that 2017 was the hottest year on record globally (without an El Niño), and among the top three hottest years overall (Click here for more on this), and scientists in China reported in the journal Cell that they had created the first monkey clones, named Zhong Zhong and Hua Hua (Click here for that news)

Zhong Zhong the cute little clone. Source: BBC

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FASN-ating PINK research

Pink

In 2018, there is one particular clinical trial that I will be watching, because the drug being tested could have a big impact on certain kinds of Parkinson’s.

The clinical trial is focused on people with cancer and they will be treated with a drug called TVB-2640TVB-2640 is an inhibitor of an enzyme called fatty acid synthase (or FAS). 

In today’s post we will discuss why TVB-2640 might be a useful treatment for certain kinds of Parkinson’s.


Mitochondria

Mitochondria and their location in the cell. Source: NCBI

 

Regular readers of this blog are probably getting sick of the picture above.

I use it regularly on this website, because a.) it nicely displays a basic schematic of a mitochondrion (singular), and where mitochondria (plural) reside inside a cell. And b.) a lot of evidence is pointing towards mitochondrial dysfunction in Parkinson’s.

What are mitochondria?

Mitochondria are the power stations of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.

How do they supply the cell with energy?

They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.

Source: Mangomannutrition

What does this have to do with Parkinson’s?

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2017 – Year in Review: A good vintage

At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective. 

2017 has been an incredible year for Parkinson’s research.

And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.

In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)


The number of research reports and clinical trial studies per year since 1817

As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.

The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).

PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.

That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.

And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.

So what happened in 2017? Continue reading

Novartis focuses on improving PARKIN control

Last week, as everyone was preparing for Christmas celebrations, researchers at the pharmaceutic company Novartis published new research on a gene that is involved with Parkinson’s, called PARKIN (or PARK2).

They used a new gene editing technology – called CRISPR – to conduct a large screening study to identify proteins that are involved with the activation of PARKIN.

In today’s post we will look at what PARKIN does, review the research report, and discuss how these results could be very beneficial for the Parkinson’s community.


Source: Novartis

As many people within the Parkinson’s community will be aware, 2017 represented the 200th anniversary of the first report of Parkinson’s disease by James Parkinson.

It also the 20th anniversary of the discovery of first genetic mutation (or variant) that increases the risk of developing Parkinson’s. That genetic variation occurs in a region of DNA (a gene) called ‘alpha synuclein’. Yes, that same alpha synuclein that seems to play such a critical role in Parkinson’s (Click here to read more about the 20th anniversary).

In 2018, we will be observing the 20th anniversary of the second genetic variation associated with Parkinson.

That gene is called PARKIN:

Title: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
Authors: Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N
Journal: Nature. 1998 Apr 9; 392(6676):605-8
PMID: 9560156

In 1998, Japanese researchers published this report based on 5 individuals from 4 Japanese families who were affected by juvenile-onset Parkinson’s. In family 1, the affected individual was a female, 43 years old, born of first-cousin parents, and her two younger brothers are healthy. Her condition was diagnosed in her teens and it had then progressed very slowly afterwards. Her response to L-dopa was very positive, but L-dopa-induced dyskinesia were frequent. In family 2-4, affected individuals (born to unrelated parents) exhibited very similar clinical features to the subject in family 1. The age of onset was between 18 to 27 years of age.

Using previous research and various techniques the investigators were able to isolate genetic variations that were shared between the 5 affected individuals. They ultimately narrowed down their search to a section of DNA containing 2,960 base pairs, which encoded a protein of 465 amino acids.

They decided to call that protein PARKIN.

PARKIN Protein. Source: Wikipedia

How much of Parkinson’s is genetic?

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Beware of the PINK-SNO(W) man!

There is a protein in most of the cells in your body called “PTEN-induced putative kinase 1″ (or simply PINK1). It plays an important role in keeping your cells healthy.

Genetic variations in the PINK1 gene have been shown to increase ones risk of developing Parkinson’s. 

This week researchers have identified a method by which the function of the PINK1 protein can be inhibited and this results in increased vulnerability to Parkinson’s. In this post, we will look at what PINK1 does, how it is inhibited, and what this could mean for the Parkinson’s community.


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Mitochondria (green) in health cells (left) and in unhealthy cells (right).
The nucleus of the cell is in blue. Source: Salk Institute

I have previously spoken a lot about mitochondria and Parkinson’s on this website.

For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are tiny bean-shaped objects within the cell. They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.

Like you and I and all other things in life, however, mitochondria have a use-by date.

As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy which is the waste disposal system of each cell).

What does this have to do with Parkinson’s disease?

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NIX-ing the PARKIN and PINK1 problem

In American slang, to ‘nix‘ something is to ‘put an end to it’.

Curiously, a protein called NIX may be about to help us put an end to Parkinson’s disease, at least in people with specific genetic mutations.

In today’s post we will look at what NIX is, outline a new discovery about it, and discuss what this new information will mean for people living with Parkinson’s disease.


Sydney harbour. Source: uk.Sydney

Before we start, I would like the reader to appreciate that I am putting trans-Tasman rivalry side here to acknowledge some really interesting research that is being conducted in Australia at the moment.

And this is really interesting.

I have previously spoken a lot about mitochondria and Parkinson’s on this website. For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are tiny bean-shaped objects within the cell. They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.

Like you and I and all other things in life, however, mitochondria have a use-by date.

As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy – the waste disposal system of each cell).

What does this have to do with Parkinson’s disease?

Well, about 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of mitophagy. Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called PARKIN and PINK1.

What do PARKIN and PINK1 do?

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O’mice an’ men – gang aft agley

This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.

The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.

In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.


The humble lab mouse. Source: PBS

Much of our understanding of modern biology is derived from the “lower organisms”.

From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.

Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.

You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.

Nor do mice. Or snails.

Or yeast for that matter.

So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.

We work with the best tools we have, but it those tools are flawed…

What did the new research report find?

This is the study:


Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
PMID: 28882997

The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.

What are induced pluripotent stem cells?

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The autoimmunity of Parkinson’s disease?

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In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.

This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.


Nature_cover,_November_4,_1869

The first issue of Nature. Source: SimpleWikipedia

The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).

Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!

On the 21st June, this report was published:

Nature
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
PMID: 28636593

In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).

What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.

In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.

Table1

Source: Nature

The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.

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